Expandable fluoropolymer device for delivery of therapeutic agents and method of making

ABSTRACT

A method of making a radially expandable fluid delivery device includes providing a tube of biocompatible fluoropolymer material with a predetermined porosity based on an extrusion and expansion forming process, applying a radial expansion force to the tube expanding the tube to a predetermined diameter dimension, and removing the radial expansion force. The tube is radially inelastic while sufficiently pliable to be collapsible and inflatable from a collapsed configuration to an expanded configuration upon introduction of an inflation force, such that the expanded configuration occurs upon inflation to the predetermined diameter dimension. The fluid delivery device is constructed of a microporous, biocompatible fluoropolymer material having a microstructure that can provide a controlled, uniform, low-velocity fluid distribution through the walls of the fluid delivery device to effectively deliver fluid to the treatment site without damaging tissue proximate the walls of the device.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 09/411,797, filed Oct. 1, 1999, which claims priority to U.S.Provisional Application Ser. No. 60/117,152, filed Jan. 25, 1999. Thisapplication claims the benefit of and priority to the aforementionedapplications (Ser. Nos. 09/411,797 and 60/117,152), which are herebyincorporated herein by reference.

BACKGROUND OF THE INVENTION

Catheter delivered inflatable balloons are utilized in a wide range ofsurgical procedures to dilate, obstruct, or restore patency to bodyvessels and organs, as well as to maintain the position of catheterdelivered instruments in vivo. Such balloons are typically attached tothe distal tip of a small diameter catheter tube to facilitate deliveryof the balloon to a treatment site within the body. The balloon isadvanced by the catheter through a body vessel while in a deflatedcondition until the balloon is appropriately positioned proximate thetreatment site. The balloon is inflated by infusing a fluid, such assaline, a contrast media, or water, into the balloon through aninflation lumen provided in the catheter. The inflated balloon isdeflated after treatment and subsequently removed from the body.

Perforated and porous catheter balloons have been proposed to delivertherapeutic agents, e.g. drugs and other medicinal agents, directly tothe treatment site while concomitantly performing their primary functionof dilation, obstruction, etc. The localized delivery of therapeuticagents to the treatment site can increase the effectiveness of thetherapeutic agent and minimize or even negate the systemic side effectsof the agent. Generally, the therapeutic agent is delivered through thewall of the catheter either through openings mechanically formed in thewall or through pores present in the material used to form the balloon.A problem common to such conventional catheter balloons is that theflow-rate and the uniform delivery of fluid, and hence the therapeuticagent, through the walls of the balloon is difficult to control.Successful delivery of the therapeutic agent to the treatment siterequires the therapeutic agent to penetrate the body tissue at thetreatment site to a depth sufficient for the agent to effect thetreatment site without effecting healthy tissue or organs proximate thetissue site. For this reason, the flow rate of and the uniform deliveryof the therapeutic agent through the walls of the balloon is important.If the flow rate is too low, the therapeutic agent can fail to properlypenetrate the tissue at treatment site. If the flow rate is too high,the therapeutic agent can be delivered to areas of the body outside ofthe treatment area and, in some cases, elevated flow rates can result inthe formation of high velocity fluid jets which can traumatize thetissue adjacent the walls of the balloon.

SUMMARY OF THE INVENTION

The present invention provides a radially expandable fluid deliverydevice for delivering fluid to a treatment site within the body. Theradially expandable fluid delivery device can be used, for example, as acatheter delivered balloon for the treatment of body lumens, organs, andgrafts. Fluids, including therapeutic agents, can be delivered throughthe walls of the fluid delivery device to effect localized treatment ofsites within the body. The fluid delivery device of the presentinvention is constructed of a biocompatible material having amicrostructure that can provide a controlled, uniform, low-velocitydistribution of fluid through the walls of the fluid delivery device toeffectively deliver the fluid to the treatment site without damagingtissue proximate the walls of the device.

In accordance with one aspect of the present invention, the fluiddelivery device comprises a member constructed of a biocompatiblematerial. The member is defined by a wall having a thickness extendingbetween an inner and an outer surface. The wall is characterized by amicrostructure of nodes interconnected by fibrils. The member isdeployable from a first, reduced diameter configuration to a second,increased diameter configuration upon the introduction of a pressurizedfluid to the lumen. The member includes at least one microporous portionhaving a porosity sufficient for the pressurized fluid to permeatethrough the wall. The spaces between the nodes control the permeation offluid through the wall of the fluid delivery device. In a preferredembodiment, substantially all of the nodes within the microporousportion are oriented such that spaces between the nodes form generallyaligned micro-channels extending from the inner surface to the outersurface of the wall.

In accordance with another aspect of the present invention, the nodeswithin the microporous portion of the member can be orientedsubstantially parallel to the longitudinal axis of the member. Themicro-channels are preferably sized to permit the passage of thepressurized fluid from the inner surface to the outer surface of thewall. The size of the microchannels within the microporous portion canbe varied longitudinally and/or circumferentially to provide regions ofincreased porosity within the microporous portion. The presence ofregions of differing porosity allows the volume of fluid deliveredthrough the microporous portion of the member to vary, longitudinallyand/or circumferentially, across the microporous portion. This allowsthe microporous portion to be specifically tailored to the size andshape of the site being treated.

Various biocompatible materials are suitable for the construction of themember. Expanded polytetrafluoroethylene (ePTFE), which is ahydrophobic, biocompatible, inelastic material having a low coefficientof friction, is the preferred material of choice.

In accordance with a further aspect of the present invention, the membercan be provided with first and second microporous portions, each havinga porosity sufficient for the pressurized fluid to permeate through thewall of the member. The first and second microporous portions can bespaced apart longitudinally and/or circumferentially. An impermeable orsemi-permeable portion can be interposed between the first and secondmicroporous portions. Further microporous portions and/or impermeable orsemi-permeable portions can also be provided on the member. Themicroporous portions and the impermeable portions can be arranged innumerous alternative configurations. For example, microporousring-shaped portions can be spaced along the longitudinal axis of themember. Alternatively, the microporous portions can be generallyrectangular in shape and can be spaced apart about the circumference ofthe member. The provision of multiple microporous portions allows thefluid delivery device of the present invention to treat multiple siteswithin the body simultaneously.

In accordance with one aspect of the present invention, a method isprovided for manufacturing a radially expandable device for delivery ofa fluid to a treatment site within the body. The method includes thestep of forming a tube of inelastic, fluoropolymer material through anextrusion and expansion process having selected process parameters. Thetube has a porosity corresponding to the selected process parameters. Aradial expansion force is applied to the tube to expand the tube from aninitial diameter to a second diameter. The expansion force is thenremoved. The resultant tube is radially expandable from a reduceddiameter to the second diameter upon application of a radial deploymentforce from a deployment mechanism within the tube. The deploymentmechanism can be, for example, a fluid injected into the tube or aradial expansion element inserted into the tube.

The tube can be constructed through an extrusion and expansion process,including the step of creating a billet by blending a mixture of afluoropolymer and a lubricant and compressing the mixture. Thefluoropolymer is preferably PTFE. The billet can then be extruded toform an extruded article. The lubricant is removed and the extrudedarticle is expanded to form a monolithic tube of inelastic, expandedfluoropolymer material. The stretched tube is then heat set to lock inthe microstructure of the tube and maintain the tube in the stretchedstate.

In accordance with a further aspect of the present invention, at leastone of the extrusion and expansion process parameters can be varied toform a microporous portion of the wall having a porosity sufficient forthe pressurized fluid to permeate through the wall. For example, thelubricant density, the lubricant viscosity, the lubricant molecularweight, the amount of lubricant and/or the longitudinal stretch ratiocan be selectively varied to form the microporous portion of the tube.The process parameters can also be varied to produce increased regionsof porosity with the microporous region or to form multiple microporousregions.

The extruded article is preferably bilaterally stretched in two opposingdirections along the longitudinal axis of the article. Bilaterallystretching the extruded article yields an article that is substantiallyuniformly stretched over a major portion of its length and has amicrostructure of nodes interconnected by fibrils. Bilateral stretchingcan further result in the formation of a microstructure in which thenodes are oriented substantially perpendicular to the longitudinal axisof the article such that the spaces between the nodes form microchannelsextending from the inner to the outer surface of the wall of the member.The bilateral stretching step can be carried out by displacing the endsof the extruded article either simultaneously or sequentially.

In accordance with another aspect of the present invention, the step ofapplying a radial expansion force to the tube is carried out byinserting a balloon into the tube and expanding the balloon to apply theradial expansion force to the tube. Preferably, the balloon isconstructed from an inelastic material such as, for example,polyethylene terephthalate (PET), nylon, or ePTFE. In a preferredembodiment, the balloon is constructed to be expandable to a predefinedsize and shape by inflation with a fluid. Radial expansion of theexpanded fluoropolymer tube with such an inelastic balloon imparts thepredetermined size and shape of the balloon to the expandedfluoropolymer balloon.

In accordance with a further aspect of the present invention, the stepof radially expanding the expanded fluoropolymer tube plasticallydeforms the tube beyond its elastic limit to the second diameter.Plastically deforming the fluoropolymer tube to the second diametercontributes to the expansion device dependably expanding to the seconddiameter upon application of the radial deployment force.

The step of radially expanding the expanded fluoropolymer tube can alsoinclude the steps of positioning the tube within the internal cavity ofa mold fixture and radially expanding the balloon within the tube whilethe tube remains positioned in the internal mold cavity. The internalmold cavity preferably has a size and shape analogous to the predefinedsize and shape of the balloon. The internal cavity of the moldfacilitates concentric radial expansion of the balloon and thefluoropolymer tube.

In accordance with a further aspect of the present invention, theradially expandable fluid delivery of the present invention isparticularly suited for treatment of body passages and grafts occludedby disease. The fluid delivery device can be utilized in the manner of acatheter balloon suitable for deployment within a body vessel by acatheter. Exemplary treatment applications of the present applicationinclude dilation of stenoic blood vessels in a percutaneous transluminalangioplasty procedure (PCA), removal of thrombi and emboli fromobstructed blood vessels, urethra dilation to treat prostaticenlargement due to benign prostate hyperplasia (BPH) or prostaticcancer, and generally restoring patency to body passages such as bloodvessels, the urinary tract, the intestinal tract, the kidney ducts, orother body passages. Exemplary therapeutic agents that can be deliveredthrough the fluid delivery device of the present invention includethrombolytics, antibiotics, antisense oligonucleotides,chemotherapeutics, surfactants, diagnostic agents, steroids,vasodilators, vasoconstrictors, and embolic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and advantages of the present invention will bemore fully understood by reference to the following detailed descriptionin conjunction with the attached drawings in which like referencenumerals refer to like elements through the different views. Thedrawings illustrate principles of the invention and, although not toscale, show relative dimensions.

FIG. 1 is a side elevational view in cross-section of a radiallyexpandable fluid delivery device according to the teachings of thepresent invention, illustrating the device in a first, reduced diameterconfiguration;

FIG. 2 is a side elevational view in cross-section of the radiallyexpandable fluid delivery device of FIG. 1, illustrating the device in asecond, increased diameter configuration;

FIG. 3 is a side elevational view of an alternative embodiment of theradially expandable fluid delivery device of the present invention,illustrating the device in the second, increased diameter configuration;

FIG. 4 is a side elevational view of an alternative embodiment of aradially expandable fluid delivery device of the present inventionhaving multiple axially-spaced microporous portions, illustrating thedevice in the second, increased diameter configuration;

FIG. 5 is a cross-sectional view of an alternative embodiment of aradially expandable fluid delivery device of the present inventionhaving an arcuate-shaped microporous portion, illustrating the device inthe second, increased diameter configuration;

FIG. 6 is a cross-sectional view of an alternative embodiment of aradially expandable fluid delivery device of the present inventionhaving multiple circumferentially-spaced microporous portions,illustrating the device in the second, increased diameter configuration;

FIG. 7 is a flow chart illustrating the steps of manufacturing a fluiddelivery device according to the teachings of the present invention;

FIG. 8 is a schematic representation of the microstructure of anexpanded fluoropolymer tube used during the manufacturing process of thepresent invention to yield the fluid delivery device of FIG. 1;

FIG. 9A is a side elevational view in cross-section of an inelasticballoon positioned within an expanded fluoropolymer tube, illustratingthe inelastic balloon in a deflated condition in accordance with amethod of manufacturing a fluid delivery device according to theteachings of the present invention;

FIG. 9B is a side elevational view in cross-section of the inelasticballoon and the expanded fluoropolymer tube of FIG. 9A, illustrating theinelastic balloon in an inflated condition in accordance with a methodof manufacturing a fluid delivery device according to the teachings ofthe present invention;

FIG. 9C is a side elevational view in cross-section of the inelasticballoon and the expanded fluoropolymer tube of FIG. 9A, illustrating theremoval of the deflated inelastic balloon from the expandedfluoropolymer tube in accordance with a method of manufacturing a fluiddelivery device according to the teachings of the present invention;

FIG. 10 is a schematic of a system for inflating an inelastic balloonwith an expanded fluoropolymer tube in accordance with a method ofmanufacturing a fluid delivery device according to the teachings of thepresent invention;

FIG. 11 is a side elevational view of an inelastic balloon and anexpanded fluoropolymer tube positioned within the internal cavity of amold fixture, illustrating the inelastic balloon in an inflatedcondition in accordance with a method of manufacturing a fluid deliverydevice according to the teachings of the present invention;

FIG. 12 is a side-elevational view in cross-section of a catheterdeployed infusion balloon according to the teachings of the presentinvention, illustrating the infusion balloon expanded within a bodyvessel;

FIG. 13 is a flow chart illustrating the steps of an alternative methodof manufacturing a fluid delivery device according to the teachings ofthe present invention;

FIG. 14A is an electron micrograph of an external section of an ePTFEtube used in the manufacture of the fluid delivery device of the presentinvention;

FIG. 14B is an electron micrograph of an external section of a fluiddelivery device of the present invention;

FIG. 14C-14D are electron micrographs of an external section of the neckof the fluid delivery device of FIG. 14B; and

FIG. 15 is a side elevational view in cross-section of a multi-layerradially expandable fluid delivery device in accordance with the presentinvention, illustrating the device in a second, increased diameterconfiguration.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A radially expandable fluid delivery device 10 having an extensiblemember 12 constructed of a biocompatible fluoropolymer material isillustrated in FIGS. 1 and 2. The radially expandable fluid deliverydevice 10 of the present invention is suitable for a wide range oftreatment applications. Such applications include use of the fluiddelivery device 10 as a catheter balloon for treatment of body passagesand grafts such as blood vessels, the urinary tract, the intestinaltract, kidney ducts, natural and synthetic grafts, etc. Specificexamples include as a device for the removal of obstructions such asemboli and thrombi from blood vessels, as a dilation device to restorepatency to an occluded body passage, as an occlusion device toselectively obstruct a body passage, and as a centering mechanism fortransluminal instruments and catheters. In each of these applications,the fluid delivery device 10 can simultaneously deliver a fluid, such asa therapeutic agent, to the body vessel, or the tissue or organssurrounding the body vessel, to effect local treatment with the agent.

The extensible member 12 of the radially expandable fluid deliverydevice 10 is deployable upon application of an expansion force from afirst, reduced diameter configuration, illustrated in FIG. 1, to asecond, increased diameter configuration, illustrated in FIG. 2. Theextensible member 12 of the fluid delivery device 10 of the presentinvention preferably features a monolithic construction, i.e., theextensible member 12 is a singular, unitary article of generallyhomogeneous material. The extensible member 12 is manufactured inaccordance with the methods of manufacturing of the present invention,an extrusion and expansion process described in detail below, to yieldan extensible member 12 characterized by a seamless construction ofinelastic, expanded fluoropolymer having a predefined size and shape inthe second, increased diameter configuration. The extensible member 12can be dependably and predictably expanded to the predefined, fixedmaximum diameter and to the predefined shape independent of theexpansion force used to expand the device.

Referring specifically to FIG. 2, the extensible member 12 of the fluiddelivery device 10 of the present invention is generally tubular inshape when expanded, although other cross sections, such as rectangular,oval, elliptical, or polygonal, can be utilized. The cross-section ofthe extensible member 12 is continuous and uniform along the length ofthe extensible member. However, in alternative embodiments, thecross-section can vary in size and/or shape along the length of theextensible member. FIG. 1 illustrates the extensible member 12 relaxedin the first, reduced diameter configuration. The extensible member 12has a central lumen 13 extending along a longitudinal axis 14 between afirst end 16 and second end 18.

A deployment mechanism in the form of an elongated hollow tube 20 isshown positioned within the central lumen 13 to provide a radialdeployment or expansion force to the extensible member 12. The tube 20can be, for example, a catheter constructed from PEBAX tubing availablefrom Elf Atochem of France. The tube 20 is selected to have an outerdiameter approximately equal to the diameter of the central lumen 13 ofthe extensible member 12 in the reduced diameter configuration. Theradial deployment force effects radial expansion of the extensiblemember 12 from the first configuration to the second increased diameterconfiguration illustrated in FIG. 2. The first end 16 and the second end18 are connected in sealing relationship to the outer surface of thehollow tube 20. The first and second ends 16 and 18 can be thermallybonded, bonded by means of an adhesive, or attached by other meanssuitable for inhibiting fluid leakage from the first and second ends 16and 18 between the walls of the extensible member 12 and the tube 20.

The hollow tube 20 includes an internal, longitudinal extending lumen 22and a number of side-holes 24 that provide for fluid communicationbetween the exterior of the tube 20 and the lumen 22. The tube 20 can becoupled to a fluid source (not shown) to selectively provide fluid, suchas water, a contrast medium, or saline, to the lumen 13 of theextensible member 12 through the lumen 22 and side-holes 24. Thepressure from the fluid provides a radial expansion force on theextensible member 12 to radial expand the extensible member 12 to thesecond, increased diameter configuration. Because the extensible member12 is constructed from an inelastic material, uncoupling the tube 20from the fluid source or otherwise substantially reducing the fluidpressure within the lumen 13 of the extensible member 12, does notgenerally result in the extensible member 12 returning to the first,reduced diameter configuration. However, the extensible member 12 willcollapse under its own weight to a reduced diameter. Application ofnegative pressure, from, for example, a vacuum source, can be used tocompletely deflate the extensible member 12 to the initial reduceddiameter configuration.

One skilled in the art will appreciate that the expansion device 10 ofthe present invention is not limited to use with deployment mechanismsemploying a fluid deployment force, such as hollow tube 20. Other knowndeployment mechanisms can be used to radially deploy the expansiondevice 10 including, for example, mechanical operated expansionelements, such as mechanically activated members or expansion elementsconstructed from temperature activated materials such as nitinol.

The extensible member 12 is defined by a wall 30 of biocompatiblefluoropolymer material having a thickness extending between an outersurface 32 and an inner surface 34 of the extensible member 12. Theinner surface 34 defines the lumen 13 of the extensible body 12. Thewall 12 of biocompatible fluoropolymer material is characterized by amicrostructure of nodes interconnected by fibrils. FIGS. 1 and 2 provideschematic representations of the microstructure of the extensible member12. For purposes of description, the microstructure of the extensiblemember has been exaggerated. Accordingly, while the dimensions of themicrostructure are enlarged, the general character of the illustratedmicrostructure is representative of the microstructure of the extensiblemember 12.

The extensible member 12 includes at least one microporous portion 40having a porosity sufficient for the flow of fluid from the lumen 13through the wall 30, i.e. from inner surface 34 to outer surface 32. Themicrostructure of the wall 30 within the microporous portion 40 ischaracterized by a plurality of nodes 36 interconnected by fibrils 38.Preferably, all or substantially all of the nodes 36 within themicroporous portion 40 are oriented perpendicular to the inner surface34 and the outer surface 32 of the extensible member 12 as well asparallel to each other. This preferred orientation of the nodes 36provides internodal spaces that form pores or micro-channels 42 thatextend between the inner surface 34 and the outer surface 32 of theextensible member 12. The micro-channels 42 are sized to permit the flowof fluid between the nodes 36 through the wall 30.

The size of the micro-channels or pores 42 can be selected through themanufacturing process of the present invention, described in detailbelow. Preferably, the internodal distance of microstructure of the wallwithin the microporous region, and hence the width of themicro-channels, is approximately 1 μm to approximately 150 μm.Internodal distances of this magnitude can yield flow rates ofapproximately 0.01 ml/min to approximately 100 ml/min of fluid throughthe wall 30 of the extensible member 12.

In a preferred embodiment, the size of the micro-channels or pores 42within the microporous portion 40 is uniform throughout the microporousportion. In this manner, the flow-rate of fluid through the wall of themicroporous portion 40 is also generally uniform. In some applications,however, it may be desirable to have an area of increased or decreasedporosity within the microporous portion such that the flow-rate can betailored to the particular geometry of the site being treated. Forexample, if a particular region at the treatment site requires increasedconcentrations of the therapeutic agent, the flow rate at thecorresponding section of the microporous portion can be increased tothereby increase the volume of therapeutic agent be delivered to theparticular region. Additionally, it is often desirable to reduce thevolume of therapeutic agent delivered to the periphery of the treatmentsite to minimize damage to healthy tissue adjacent the site. The poresize within the microporous region thus can be varied axially orcircumferentially, or both, to form such areas of increased or decreasedporosity.

The terms “axial” and “axially” as used herein refers to a directiongenerally parallel to the longitudinal axis of the extensible member 12.The terms “circumferential” and “circumferentially” as used hereinrefers to a direction generally parallel to the circumference of theextensible member 12. The explanation of these terms is not, however, tobe construed to limit the extensible member 12 to a circularcross-section. As discussed above, the cross-section can be any of anumber shapes. In the case of non-circular cross-sections, the terms“circumferential” and “circumferentially” as used herein to generallyrefer to a direction parallel to the perimeter of the extensible member.

The axial length, as well as the axial position, of the microporousportion 40 of the extensible member 12 can be varied to accommodatespecific treatment applications. As illustrated in FIG. 2, for example,the microporous portion 40 can extend along the entire inflatable lengthof the extensible member 12. In particular, the microporous portion 40includes a section 40 b that is oriented parallel to the longitudinalaxis 14 of the extensible member 12 as well as two spaced apart taperedsections 40 b and 40 c. In the embodiment illustrated in FIG. 2, thus,the microporous portions 40 a, 40 b, and 40 c extend along the entirelength of the extensible member 12, absent the first and second ends 16and 18, which are sealed to the hollow tube 20.

The microporous portion 40 need not extend the entire inflatable lengthof the extensible member 12 but instead can include only sections of thelength of the extensible member 12. For example, as illustrated in FIG.3, the microporous portion can include only section 40 b, the sectionoriented parallel to the longitudinal axis 14 of the extensible member12. Tapered section 44 and 46 adjacent the microporous portion 40 b canbe substantially impermeable to the fluid within the extensible member12. The tapered sections 44 and 46 can formed with the samemicrostructure as the microporous portions 40 b, i.e. nodes of the samesize and orientation, and can be sealed with a coating provided on theinner surface 34 or the outer surface 32 to inhibit fluid flow throughthe sections 44 and 46. Alternatively, the microstructure of the taperedsections 44 and 46 can have an impermeable, non-porous structure. Forexample, the nodes forming the microstructure of the tapered sections 44and 46 can be spaced apart or oriented to inhibit or prevent fluid frompassing therethrough.

Moreover, two or more microporous portions of similar or different axiallengths can be provided on the extensible member 12. For example, theextensible member 12 can be provided with three axially spacedmicroporous portions 40 e, as shown in FIG. 4. Each of the microporousportions 40 e is bordered axially by an impermeable portion 48. Themicroporous portions 40 e provide porous, fluid permeable annular zonesthat are spaced lengthwise along the extensible member 12. Themicroporous portions 40 e can be equally spaced and of similar size, asillustrated in FIG. 4, or, in the alternative, can be distinctly sizedand spaced. One skilled in the art will appreciate that the number ofindependent microporous portions is not limited to three as shown inFIG. 4, but can include two or more zones as dictated by the length ofthe extensible member 12 and the desired size of the microporousportions.

Referring to FIGS. 5 and 6, the size and position of the microporousportion can be varied circumferentially as well as axially. For example,the microporous section need not extend about the entire circumferenceof the extensible member 12. FIG. 5 illustrates an alternativeembodiment in which the microporous portion 40 f generally extends aboutone-half of the circumference of the extensible member to form anarc-shaped section that is permeable to fluid within the extensiblemember 12. An impermeable arc-shaped section 50 is positioned adjacentthe arc-shaped microporous portion 40 f. Additionally, two or moremicroporous portions can be spaced circumferentially about theextensible member 12. FIG. 6 shows an alternative embodiment includingfour equally spaced arcuate microporous portions 40 g. Arc-shapedimpermeable portions 52 are spaced between the microporous portions 40g. As in the case of the embodiments described above, the microporousportions 40 g can be equally spaced and of similar size, as illustratedin FIG. 6, or, in the alternative, can distinctly sized and spaced.Further, the number of microporous portions described is exemplary only;the number of microporous portions is limited only by the circumferenceof the extensible member 12 and the desired size of the microporousportions.

The impermeable sections of each of the embodiments described above canbe constructed of the same microstructure as the microporous portionsadjacent thereto, i.e. nodes having the same size and orientation. Theimpermeable sections can be made impermeable by sealing the sectionswith a coating provided on either the inner surface 34 or the outersurface 32, or both, to inhibit or prevent fluid flow through thesections. Alternatively, the microstructure of the impermeable sectionscan be constructed to have an inherently impermeable, non-porousstructure. For example, the nodes forming the microstructure of theimpermeable sections can be spaced apart or oriented to inhibit orprevent fluid from passing therethrough.

Various fluoropolymer materials are suitable for use in the presentinvention. Suitable fluoropolymer materials include, for example,polytetrafluoroethylene (PTFE) or copolymers of tetrafluoroethylene withother monomers may be used. Such monomers include ethylene,chlorotrifluoroethylene, perfluoroalkoxytetrafluoroethylene, orfluorinated propylenes such as hexafluoropropylene. ePTFE is thepreferred material of choice. Accordingly, while the fluid deliverydevice 10 can be manufactured from various fluoropolymer materials, andthe manufacturing methods of the present invention can utilize variousfluoropolymer materials, the description set forth herein refersspecifically to ePTFE.

A method of manufacturing a fluid delivery device in accordance with thepresent invention will be described in connection with the flow chartshown in FIG. 7. The fluid delivery device 10 of the present inventionis produced from a tube constructed of expanded fluoropolymer material,which is preferably produced through an extrusion and a longitudinalexpansion process. The preferred fluoropolymer material is expanded PTFE(ePTFE), which is a hydrophobic, biocompatible, inelastic materialhaving a low coefficient of friction, although, as discussed above,other inelastic, biocompatible fluoropolymer materials may be used.

To produce the ePTFE tube, a billet comprising a PTFE resin mixed withan organic lubricant is utilized. Various organic lubricants aresuitable such as naphtha, ISOPAR-G and ISOPAR-H available from ExxonCorporation. The blended resin is compressed at low pressure to yield atubular billet of PTFE resin and lubricant, step 210 of FIG. 7. Thetubular billet is then extruded through an extruder, for example a ramextruder, to reduce the cross section of the billet and to yield atubular extrudate, step 212. The organic lubricant can be removed fromthe extrudate by drying the extrudate in a heated oven, step 214.

Once the tubular extrudate is produced, the extrudate is expanded bylongitudinal stretching, step 216. Preferably, the extrudate isbilaterally stretched. Bilateral stretching is accomplished bydisplacing both ends of the extrudate, sequentially or simultaneously,away from the center of the extrudate. Bilateral stretching provides amaterial that is homogeneously stretched over the majority of its lengthand yields a uniform porosity over the length of the material. After theextrudate has been stretched, it is heat set to lock in themicrostructure of the material, step 218 of FIG. 7, and to complete theprocess of the forming the tube 110 of ePTFE.

FIG. 8 is a schematic representation of the ePTFE tube 110 as formed bythe extrusion and expansion process described above. For purposes ofdescription, the microstructure of the tube 110 has been exaggerated.Accordingly, while the dimensions of the microstructure are enlarged,the general character of the illustrated microstructure isrepresentative of the microstructure prevailing within the tube 110.

The microstructure of the ePTFE tube 110 is characterized by nodes 130interconnected by fibrils 132. The nodes 130 are generally aligned withone another and are generally oriented perpendicular to the longitudinalaxis 114 of the tube 110. Substantially all of the nodes 130 extendalong a transverse axis 134 from an inner surface 136 to an outersurface 138 of the tube 110. This microstructure of nodes 130interconnected by fibrils 132 provides a microporous structure havingmicrofibrillar spaces which define generally aligned through-pores orchannels 134 extending entirely from the inner wall 136 and the outerwall 138 of the tube 110. The through-pores 134 are perpendicularlyoriented (relative to the longitudinal axis 114), internodal spaces thattraverse from the inner wall 136 to the outer wall 138. The size andgeometry of the through-passages can be altered through the extrusionand expansion process, to yield a microstructure that is impermeable,semi-impermeable, or permeable.

Although it is preferable for the micro-channels of the ePTFE tube 110,and the resultant fluid delivery device 10, to be oriented generallyperpendicular to the longitudinal axis of the tube ePTFE 110 or fluiddelivery device 10, other orientations of the micro-channels can beutilized. For example, by twisting or rotating the ePTFE tube during theextrusion and/or stretching process, the micro-channels can be orientedat an angle to an axis perpendicular to the longitudinal axis of thetube.

In a preferred embodiment, the ePTFE tube 110, and the resultant fluiddelivery device 10, has a fine nodal structure that is uniformthroughout the cross section and length of the ePTFE tube. The preferreduniform fine nodal structure provides the fluid delivery device 10 withimproved expansion characteristics as the expandable device dependablyand predictably expands to the second diameter. The preferred fine nodalstructure is characterized by nodes having a size and mass less than thenodes found in conventional ePTFE grafts, preferably in the range of 25μm to 30 μm. Additionally, the spacing between the nodes, referred to asthe internodal distance, and the spacing between the fibers, referred toas the interfibril distance, is also preferably less than found inconventional ePTFE grafts, preferably in the range of 1 μm to 5 μm.Moreover, the internodal distance and the interfibril distance in thepreferred embodiment is preferably uniform throughout the length and thecross section of the ePTFE tube. The preferred uniform nodal structurecan be created by forming the billet with a uniform lubricant levelthroughout its cross section and length. Stretching the tubularextrudate at higher stretch rates, for example at rates greater than 1in/s, yields the preferred fine nodal structure. Preferably, theextrudate is stretched at a rate of approximately 10 in/s or greater.

Continuing to describe the manufacturing method of the present inventionand referring to FIGS. 7 and 9A, the ePTFE tube 110, having an initialdiameter d, is pulled over a balloon 112 to position the balloon 112within the lumen 114 of the tube 110, step 220 of FIG. 7. The balloon112 is preferably constructed of an inelastic material such as, forexample, PET, nylon, or PTFE, such that the balloon 112, when inflated,attains a predetermined size and shape. The balloon 112 can be bonded orotherwise coupled to a rigid catheter or hypo-tube 116 to facilitateplacement and removal of the ePTFE tube as described below. The catheter116 has a central inflation lumen 118 and a plurality of side-holes 120to provide for the delivery of an inflation fluid to inflate the balloon112. Prior to placement of the ePTFE tube 110 over the balloon 112, asmall amount of negative pressure (vacuum) can be applied to the balloon112 to reduce the balloon to a minimum deflated profile.

Referring to FIG. 10, a system 148 for inflating the balloon 112 withinthe ePTFE tube is illustrated. The balloon 112 and the ePTFE tube 110are positioned within water heated chamber 150, step 222 of FIG. 6. Thecatheter 116 is connected by plastic tubing 152 to a pump 154, such asan ISCO syringe pump, for inflation of the balloon 112 with a fluid.Heated water from a circulating temperature bath 158 is pumped throughthe chamber 150 by a pump 160 to maintain the water within the chamber150 at a desired temperature. The water within the chamber 150 is heatedto a temperature between approximately 35° C. and approximately 60° C.The preferred temperature of the water within the chamber 150 is 50° C.The constant, elevated temperature provided by the circulating water cancontribute to uniform expansion, both circumferentially andlongitudinally, of the ePTFE balloon, as well as uniform wall thickness.

Referring to FIGS. 9B and 10, the balloon 112 can be inflated byintroduction of pressurized fluid from the pump 154 to the lumen 114 ofthe ePTFE tube 110. The overlying ePTFE tube 110 expands with theinelastic balloon 122 until both the balloon 112 and the ePTFE tube 110obtain the predetermined size and shape of the inflated balloon 112,step 224 of FIG. 7. The inflated balloon 112 thus imparts itspredetermined size and shape to the ePTFE tube 110. This radiallyexpansion process is referred to as “blow-molding”. The PTFE tube 110shown in FIG. 9B is radially expanded from the initial diameter d (FIG.9A) to an increased diameter D.

It is preferable for the ePTFE tube 110 to be plastically deformed bythe radial expansion of the inelastic balloon 112, step 226 of FIG. 7.The terms “plastic deformation” and “plastically deform,” as usedherein, is intended to include the radial expansion of the ePTFE tube110 beyond the elastic limit of the ePTFE material such that the ePTFEmaterial is permanently deformed. Once plastically deformed, the ePTFEmaterial forming the tube 110 becomes substantially inelastic, i.e., theePTFE tube generally will not, on its own, return to its pre-expansionsize and shape.

The ePTFE tube 110 can be removed from the balloon 112 by removing theinflation fluid from the balloon 112 using the pump 154 and sliding theePTFE tube 110 relative to balloon 112 and catheter 116, i.e. in thedirection of arrows A in FIG. 9C, step 228 of FIG. 7. The tube 110 canbe heat set at a temperature above the sinter point of the materialforming the tube, 360° C. for ePTFE, to lock in the structure of thetube 110, step 230 of FIG. 7. The pump 150 can be used to provide aslight vacuum within the balloon 112 to facilitate removal of the ePTFEtube 110.

The ePTFE tube 110 can be attached to a deployment mechanism such ashollow tube 20 described above, step 232 of FIG. 7. A suitable adhesivecan be used to secure the ePTFE tube to the deployment mechanism.

Referring to FIG. 11, an alternative method of manufacturing a radiallyexpandable device employing a mold 202 is illustrated. The mold 202includes two interconnected sections 204 and 206 forming an internalmold cavity 208 for receiving the ePTFE tube 110 with the balloon 112positioned therein. The mold 202 is preferably constructed of a rigid,unyielding material such as a metal or metal alloy. Suitable metals ormetal alloys include brass and steel alloys. The internal mold cavity208 preferably has a size and shape analogous to that of the inflatedballoon 112 to ensure that the inflated balloon 112, and the overlyingePTFE tube 110 concentrically expand.

Referring to the flow chart illustrated in FIG. 13, a furtheralternative method of manufacturing a fluid delivery device according tothe teachings of the present invention will be described. A tubeconstructed of ePTFE is formed in accordance with the methods describedabove, step 410. A tube formed of an extruded inelastic material such asPET is used in place of balloon 112 to radially expand the ePTFE tube.The extruded tube is positioned within the ePTFE tube 110, step 412. Theextruded tube is then sealed at one end and attached to an inflationsystem at the other end, step 414. The extruded tube can then beinflated by an inflation medium to radially expand the ePTFE tube, step416. The extruded tube and ePTFE tube are preferably heated to the glasstransition temperature of the extruded tube, approximately 80° C.-100°C. for PET, as the extruded tube is inflated within the ePTFE tube. Itis preferable to limit the temperature of the extruded tube to atemperature less than or equal to the glass transition temperature ofthe material forming the extruded tube to facilitate removal of theextruded tube from the ePTFE tube. Heating the extruded to a temperatureabove the glass transition temperature will cause the extruded tube toheat set in an expanded configuration, which makes removing the extrudedtube from the ePTFE tube difficult.

After the extruded tube and ePTFE tube are expanded to desired size andshape, the extruded tube is deflated and removed from the ePTFE tube,step 418. The ePTFE tube is then heat set to lock in the structure ofthe ePTFE tube, step 420.

A mold, such as mold 202, can be employed during radial expansion of theePTFE tube using the PET tube. The mold is preferably heated within thehot water chamber of an inflation system, such as inflation system 148illustrated in FIG. 10, or by other means such as a hot oil bath orthrough a steam, hot air, electric, radio frequency or infra red heatsource. The mold can be constructed of a material having good headtransfer characteristics, such as metal or metal alloy, for examplebrass. The mold includes a mold cavity having a size and shape analogousto the desired size and shape of the fluid delivery device 10 in thesecond diameter configuration.

The resultant radially expanded ePTFE tube 110, produced in accordancewith the above described methods, provides a radially expandable fluiddelivery device, such as the fluid delivery device 10 illustrated inFIGS. 1 and 2 and described above, that is radially expandable from arelaxed, collapsed diameter to the second, increased diameter D uponapplication of a radial deployment force from a deployment mechanismwithin the tube 110. Moreover, the microstructure of the radiallyexpanded ePTFE tube 110 can be manufactured through the process of thepresent invention to have a porosity sufficient to permit fluid to flowtherethrough. In particular, the microstructure of the resultant fluiddelivery device is analogous to the microstructure of the ePTFE tube110, i.e. nodes interconnected by fibrils, the space between the nodesdefining micro-channels through the wall of the device.

One feature of the manufacturing processes of the present invention isthat the microporous structure of the ePTFE tube 110 forming the fluiddelivery device 10 can be manipulated by varying the extrusion andexpansion process parameters to produce different porositycharacteristics. For example, the longitudinal stretch ratio of theePTFE tube 110, i.e., the ratio of final stretched length of the tube tothe initial length, and the diametric stretch ratio of the ePTFE tube110, i.e., the ratio of the final diameter, after longitudinalstretching, and the initial diameter, and the stretch rate can be variedto yield fluid recovery devices having different porosity. Applicantsdetermined that larger longitudinal stretch ratios, in the order of 2:1to 3:1, can result in a ePTFE tube having a microstructure characterizedby increased internodal distances and interstitial space, i.e., themicro-channels within the microstructure of the ePTFE tube are increasein sized. Suitable longitudinal stretch ratios can be from 1.1:1 to10:1.

Fluid delivery devices formed from ePTFE tubes having larger stretchratios require minimal fluid pressure within the device to achieve thedesired flow rate of fluid through the walls of the device. Such fluiddelivery devices will consequently provide little radially-outwarddilation force, which can be advantageous for some applications such asdelivering therapeutic or diagnostic agents to healthy tissue.Conversely, ePTFE tubes having smaller stretch ratios result in fluiddelivery devices that are less porous, as the internodal distances arereduced, and, thus, generally require increased fluid pressure todeliver the fluid. Such fluid delivery devices consequently provideincreased radially outward dilation force, which can be advantageous fortreatment applications such as reducing arterial lesions with pressure.Accordingly, the porosity of the ePTFE tube, and hence the porosity ofthe resultant fluid delivery device, is dependent on the stretch ratiosof the expansion process. By manipulating the stretch ratios of theePTFE tube, i.e. increasing or decreasing the stretch ratios, theporosity of the fluid delivery device can be tailored to the specifictreatment application.

The porosity of the ePTFE tube, and the subsequent fluid deliverydevice, can also depend on the density, the viscosity, the molecularweight, and the amount of lubricant used to form the billet used in theextrusion and expansion process. Increasing the amount by weight oflubricant or increasing the density or molecular weight of thelubricant, results in an extrudate having increased internodal distancesand interstitial spaces prior to the step of expansion. Once stretched,the resultant ePTFE tube will reflect the increased porosity.

The process described above can be used to produce fluid deliverydevices having a uniform porosity though out the length of the device.To produce discrete microporous portions within the fluid deliverydevices a number of different processes can be employed. For example, acoating can be applied at select locations to the inner and/or outersurfaces of the fluid delivery device to produce impermeable sectionswithin the device. The coating preferable seals the microchannels withinthe microstructure of the device to inhibit or prevent fluid frompassing therethrough.

Alternatively, the porosity of the ePTFE tube can be selectively reducedsubsequent to the step of expansion by applying heat to the selectsections of the tube to return the sections to the pre-stretchedporosity. The selectively heated sections will thus yield sections ofreduced porosity. By controlling the amount of heat applied, thesections of reduced porosity can be made semi-permeable or impermeableto fluid.

In addition to selecting and varying the porosity of the fluid recoverydevice through the manufacturing process of the present invention, theparameters of the manufacturing process can be varied to produce anePTFE tube having distinct expansion characteristics. The size and shapeof the fluid recovery device of the present invention can also bevaried. These processes are described in detail in Applicants' U.S. Pat.No. 6,395,208, which is incorporated herein by reference.

FIG. 12 illustrates an exemplary embodiment of the fluid delivery deviceof the present invention in which the fluid delivery device 10 of FIG. 1is utilized as a catheter deployed dilation and diffusion balloon 300for the treatment of a blood vessel 310 partially occluded by plaquedeposits 312 adhered to the walls 314 of the blood vessel. Thisprocedure is generally referred to as a Percutaneous TransluminalAngioplasty (PTA) procedure. The balloon 300 can be manufactured inaccordance with the methods of the present invention and is shown in theexpanded configuration. The ends 302 of the dilation balloon 300 arebonded to a catheter tube 320, which is used to provide an inflationfluid to the balloon 300 to effect expansion of the balloon 300 to apredefined and fixed maximum diameter. A therapeutic agent, such asantisense oligonucleotides (AS-ODNs), can be delivered through the wallsof the balloon with the inflation fluid. The AS-ODNs are deliveredlocally to the walls of the body vessel to suppress restenosis of thebody vessel subsequent to the PTA procedure.

A variety of therapeutic agents can be delivered with the fluid deliverydevice of the present invention. Exemplary therapeutic agents include:thrombolytics, antibiotics, chemotherapeutics, surfactants, diagnosticagents, steroids, hot saline, vasodilators, vasoconstrictors, andembolic agents. The localized delivery of thrombolytics, such asheparin, and urokinase, directly to the surface of thrombosed grafts ornative body vessels can inhibit the—clotting of the graphs or nativebody vessels. The fluid delivery device of the present invention thuscan be used as thrombolectomy balloon catheter to remove obstructionsfrom grafts or native body vessels while concomitantly deliveringthrombolytics to the walls of the graft or native body vessel.

The fluid delivery device of the present invention can further be usedfor the localized delivery of high concentrations of antibiotics totreatment sites such as the ear canal, the throat, and the upperrespiratory passages. Anti-cancer agents such as chemotherapeuticsdelivered using the fluid delivery device of the present invention canincrease the effectiveness and negate the systemic side effects of theanti-cancer agents. Exemplary forms of cancer targeted for thisapplication can include: rectal, esophageal, and lung cancer.Surfactants can be delivered directly to the lungs using the fluiddelivery device of the present invention to treat cystic fibrosis orhyaline membrane disease. Diagnostic agents can be delivered duringangiography procedures through the fluid delivery device of the presentinvention to improve the visibility of contrast agents delivered locallyto the treatment site. The local delivery of steroids, such as anabolicsteroids, using the fluid delivery device of the present invention canincrease the effectiveness, e.g., promote muscle recovery, and negatesystemic side effects such as lung and adrenal gland vantage.

The fluid delivery device of the present invention can also be providedwith hydrophilic or hydrophobic coatings dependant on the particulartreatment applications. For example, fluid delivery devices constructedof ePTFE, a naturally hydrophobic material, can be coated with ahydrophilic coating to provide the fluid delivery device with ahydrophilic outer surface. A suitable hydrophilic coating is PHOTOLINKavailable from Surmodics of Eden Prairie, Minn.

In an alternative embodiment illustrated in FIG. 15, the fluid deliverydevice of the present invention can be provided with multiple layers.The multi-layer fluid delivery device 500 includes a first layer 502 ofbiocompatible material, such as ePTFE, and a second layer 504 ofbiocompatible material that overlies the first layer 502. The secondlayer 504 can be constructed from the same or a different biocmopatiblematerial than the first layer 502. As shown in FIG. 15, the first layer502 and the second layer 504 are preferably coexentsive, however, thesecond layer 504 need not extend the entire length of the first layer502. Likewise, the first layer 502 may be smaller in length than thesecond layer 504.

The first layer 502 and the second layer 504 can each be formed from aseparate ePTFE tube. The ePTFE tubes can be constructed in accordancewith the manufacturing methods of the present invention such that eachtube is characterized by a microstructure of nodes interconnected byfibrils. Preferably the nodes are oriented generally perpendicular tothe longitudinal axis. The two ePTFE tubes can then be coaxiallydisposed and heated to bond the two tubes together. The bonded tubes canbe radially expanded by a balloon in accordance with the abovemanufacturing methods of the present invention. By producing the ePTFEtubes forming the first and second layers using different processparameters, e.g. different stretch ratios or stretch rates, the distancebetween the nodes can varied between the ePTFE tubes. For example, theinternodal distances of the microstructure of the first layer 502 can begenerally greater than the internodal distances of the microstructure ofthe second layer 504. In this manner, the porosity of the first layer502 and the porosity of the second layer 504 can be different.

Although the multi-layer fluid delivery device 500 illustrated in FIG.15 includes two layers, additional layers can be provided. Additionallayers can be formed from further ePTFE tubes or through other methods,such as by wrapping ePTFE film about the first layer and/or secondlayer.

Example 1

An exemplary fluid delivery device was constructed according to themanufacturing processes of the present invention by employing0.068″(ID)/0.088″(OD) ePTFE tubing. The longitudinal stretch ratio ofthe ePTFE tube was 1.5:1, at a stretch rate of 10 inches per second. Anelectron micrograph of an exterior section of a sample ePTFE tube, afterstretching, is shown in FIG. 14A. FIG. 14A illustrates themicrostructure of nodes interconnected by fibrils of the ePTFE tubingand, in particular, the orientation of the nodes generally perpendicularto the longitudinal axis of the tubing and the internodal through-pores.An 8 mm×8 cm PET balloon was employed to radially expand the ePTFEtubing. The PET balloon was attached to a vacuum source and a slightvacuum was placed on the PET balloon, about −5 to −10 psi. The ePTFEtubing was then positioned over the deflated PET balloon. The PETballoon and the ePTFE tubing were then connected to a hypo-tube andplaced into a water heated chamber. Saline was injected into the PETballoon at a constant flow rate of about 10-15 ml/min. When the pressurewithin the balloon reached 70-80% of the rated balloon pressure, about12-15 atm for the PET balloon employed, the flow rate was decreased to 2ml/min. The balloon was then brought to its rated balloon pressure. Thewater was then removed from the PET balloon using the pump until aslight vacuum existed within the PET balloon (−5 to −10 psi). Thehypo-tube was then removed from the chamber and the ePTFE tube waswithdrawn from the balloon. The proximal I.D. of the resultant ePTFEtube was approximately ⅔ Fr larger than the distal I.D.

The resultant ePTFE balloon was then allowed to completely dry. TheePTFE balloon was cut to a desired length and the proximal tail of theePTFE balloon was dipped into Loctite 7701 Prism Primer, available fromLoctite, Corp. of Rocky Hill, Conn. The distal tail of the ePTFE balloonwas then dipped into the primer. The primer was allowed to evaporate forat least two minutes. The ePTFE balloon was then placed on a 5 Fr-4 Frtipped catheter by pulling the proximal end of the ePTFE balloon ontothe 5 Fr end of the catheter body until the distal (4 Fr) end is about0.1″ from the tip of the catheter. The location of the proximal tail ofthe ePTFE balloon was then marked on the catheter and the ePTFE balloonwas removed from the catheter. Loctite 4011 adhesive was then applied tothe catheter shaft at a location slightly distal to the marked position.The ePTFE balloon was then slid back onto the catheter shaft until theproximal end was aligned with the mark. The adhesive was allowed to dryfor one minute. A small volume of Loctite 4011 adhesive was dispensedonto the distal end of the catheter shaft adjacent to the distal end ofthe ePTFE balloon. This adhesive was drawn into the gap between thecatheter and the balloon by capillary forces. The adhesive was thenallowed to dry for at 24 hours.

An electron micrograph of an exterior section of a sample ePTFE balloonis shown in FIGS. 14B-14D. FIG. 14B illustrates the microstructure ofnodes interconnected by fibrils of the body of the ePTFE balloon. FIGS.14C and 14D are cross-sections of the neck of the ePTFE balloon atvarying magnifications. FIGS. 14B-14D illustrate the internodalthrough-pores or channels of the ePTFE balloon as defined by themicrofibrillar spaces between the nodes. The through-pores are orientedgenerally perpendicular to the longitudinal axis of the ePTFE balloonand provide fluid pathways between the inner surface and the outersurface of the ePTFE balloon.

Example 2

Three ePTFE synthetic grafts were treated using an ePTFE diffusionballoon constructed in accordance with the method of Example 1 todetermine the permeability of a contrast agent into the grafts. Thediffusion balloon employed was 8 cm in length, had an OD of 6 mm and wasconstructed from an 0.088″(OD)/0.068″ (ID) ePTFE tube having a stretchratio of 1.5:1. Each of the grafts treated was an Atrium Hybrid PTFEgraft, model no. 01200670, available from Atrium Medical of Hudson, N.H.The grafts had a 6 mm inner diameter and a wall thickness of 0.025inches. In each case, the balloon was inserted into a graft and inflatedby infusing a contrast agent. The balloon was inflated to 1 atm. by theinfused fluid. The balloon was then removed from the graft and the graftwas flushed with water delivered at 500 ml/min. The contrast agent usedwas Hypaque-76 available from Mycomed, Inc. Table 1 summarizes eachprocedure.

TABLE 1 Duration of Balloon Balloon Infusion Graft Flushing Graft SampleInfusion Fluid Duration 1 15 seconds Saline & Contrast  5 minutes Agent2 15 seconds Saline & Contrast 30 seconds Agent 3 15 seconds Saline NoFlushing (Control)

X-rays were taken of each of the grafts samples to determine if thecontrast agent was present in the grafts post infusion and perfusion(flushing). Table 2 summarizes the results of the X-rays for each graft.

TABLE 2 Graft Sample Presence of Contrast Agent 1 Yes 2 Yes 3 No

Contrast agent was found in the walls of the both ePTFE graft samplesinfused with contrast agent by the diffusion balloon of the presentinvention, but not in the control sample. In graft samples 1 and 2, thecontrast agent was found to have permeated through the entire wall ofthe graft. Flushing the grafts with water post infusion was determinedto have no effect on the presence and concentration of the deliveredcontrast agent.

Example 3

The permeability of several ePTFE fluid delivery devices constructed inaccordance with the manufacturing processes of the present invention wasevaluated and compared with the permeability of selected syntheticgrafts. Each of the fluid delivery devices was constructed from anextruded and expanded ePTFE tube as set forth in Table 3.

TABLE 3 Fluid Stretch Rate Wall Delivery Stretch Ratio of Thickness ofSurface Area of Device of ePTFE ePTFE tube Fluid Delivery Fluid DeliverySample tube (in/s) Device (in) Device (in²) 1 1.5:1 20 0.0068 0.456 21.75:1  10 0.0055 0.469 3   3:1 10 0.005 0.469 4 5.1 10 0.003 0.503 51.25:1  10 0.0075 0.399 6 1.5:1 0.5 0.0055 0.399 7 1.5:1 10 0.005 0.3998 1.5:1 10 0.005 0.29

The synthetic grafts analyzed were standard and thin wall graftsavailable from Atrium Medical Corporation and W. L. Gore & Associates,Inc. Information regarding the grafts is set forth in Table 4

TABLE 4 Graft sample Type Wall Thickness (in) Surface Area (in²) AAtrium 6 mm std 0.025 0.964 B Atrium 6 mm thin 0.022 0.963 C Gore 7 mmthin 0.016 1.143 D Gore 6 mm std 0.024 0.963 E Gore 4 mm 0.025 0.59 FAtrium 4 mm 0.02 0.49

The fluid delivery devices and the synthetic grafts were infused with afluid to determine the permeability of the samples. The permeability ofeach of the samples is reflected by the hydrodynamic resistance and thehydraulic conductivity data set forth in Table 5.

TABLE 5 Hydrodynamic resistance Hydraulic Conductivity Sample (psi *min * mL⁻¹) (cm⁴/(dyne * s) * 10¹²) 1 21.2 67 2 7.18 155 3 2.76 368 42.81 202 5 13.4 134 6 1.59 825 7 1.5 795 8 1.7 966 A 2.394 1031 B 1.032112 C 0.711 1874 D 0.623 3808 E 1.5 2673 F 1.2 3207

Hydraulic conductivity was determined using Darcy's Law for describingsteady flow through a porous media. Darcy's law is defined in Equation 1as

Q/A=−K(ΔP/ΔX),  (Eq. 1)

where Q is flow rate, A is cross sectional area for flow, i.e. thesurface area of the sample, P is pressure, X is wall thickness, and K isthe hydraulic conductivity.

Applicants determined that the permeability of a fluid delivery devicerelative to the permeability of the vessel being treated is an importantconsideration in establishing effective fluid delivery into the walls ofthe vessel. In particular, for a given fluid flow rate and pressure, agreater volume of fluid will penetrate the walls of a vessel beingtreated if the permeability of the vessel is greater than thepermeability of the fluid delivery device. Accordingly, it is desirablefor the permeability of the fluid delivery device to be less than thepermeability of the vessel being treated. The permeability of the fluiddelivery device can be tailored to be less than the vessel being treatedby varying the process parameters of the manufacturing processesdescribed above. The process parameters include lubricant density,lubricant viscosity, lubricant molecular weight, longitudinal stretchratio, and stretch rate.

The permeability data set forth in Table 5 illustrates that thepermeability, when measured in terms of the hydraulic conductivity, foreach of the fluid delivery devices tested was less than the permeabilityof each of the synthetic grafts tested. This indicates that theApplicants' fluid delivery device may be particularly effective fordelivering fluid to the walls of synthetic grafts.

Applicants have determined that it is desirable for the hydraulicconductivity of the fluid delivery device to be less than, 1000(cm⁴/(dyne*s)*10¹²) for treatment of synthetic grafts. Preferably, thefluid delivery device has a hydraulic conductivity of less than 500(cm⁴/(dyne*s)*10¹²). For treatment of natural body vessels and grafts,it is preferable for the hydraulic conductivity of the fluid deliverydevice to be less than 100 (cm⁴/(dyne*s)*10¹²).

It will thus be seen that the invention efficiently attains the objectsmade apparent from the preceding description. Since certain changes maybe made in the above constructions without departing from the scope ofthe invention, it is intended that all matter contained in the abovedescription or shown in the accompanying drawings be interpreted asillustrative and not in a limiting sense.

It is also to be understood that the following claims are to cover allgeneric and specific features of the invention described herein, and allstatements of the scope of the invention which, as a matter of language,might be said to fall therebetween.

Having described the invention, what is claimed as new and desired to besecured by Letters Patent is: 1-20. (canceled)
 21. A method ofdelivering one or more therapeutic agents to a body passage or locationin need of treatment, comprising the steps of: substantially controllingpermeation of fluid through a wall of a radially expandable fluiddelivery device by predetermining porosity of the wall, wherein the wallhas at least one microporous portion comprising micro-channels so thewall has a porosity sufficient for a fluid to expand the fluid deliverydevice and permeate through the micro-channels; locating the radiallyexpandable fluid delivery device within a body passage or a location inneed of treatment; and expanding the radially expandable fluid deliverydevice with a fluid containing the one or more therapeutic agents sothat the fluid containing the one or more therapeutic agents isdelivered through the micro-channels of the wall of the radiallyexpandable fluid delivery device to the body passage or location. 22.The method according to claim 21, wherein the expansion of the radiallyexpandable fluid device with the fluid containing the one or moretherapeutic agents includes radial expansion of the fluid deliverydevice.
 23. A method of manufacturing a radially expandable fluiddelivery device, comprising the steps of: applying a radial expansionforce to a tube so as to expand the tube to a predetermined diameterdimension, wherein the tube comprises a biocompatible fluoropolymermaterial having a microstructure of nodes interconnected by fibrils,wherein the microstructure has a predetermined porosity based on anextrusion and expansion forming process; and removing the radialexpansion force, wherein the tube is radially inelastic whilesufficiently pliable to be collapsible and inflatable from a collapsedconfiguration to an expanded configuration upon introduction of aninflation force so that the expanded configuration occurs upon inflationto the predetermined diameter dimension.